3-(2-hydroxyethyl)-4-methyl-5-phenyloxazolidine and certain esters



United States Patent Ofice Patented May 16, 1961S-(Z-HYDROXYETHYL)-4-METHYL-5-PHENYLOXA- ZOLlDINE AND CERTAIN ESTERS MaxJ. Kalm, Skokie, and Kurt J. Rorig, Glenview, Ill.,

assignors to G. D. Searle & (30., Chicago, 111., a corporation ofDelaware No Drawing. Filed July 29, 1959, Ser. No. 830,208 Claimspriority, application Canada July 31, 1958 4 Claims. (Cl. 260-307) Thisinvention relates to 3 (2-hydroxyethyl) -4-methyl- 5-phenyloxazolidine,its esters, and processes for the manufacture thereof. Moreparticularly, this invention relates to compounds of the formula moN-omomo-n II -Clower alkyl wherein the lower alkyl constituent is suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tertbutyl, pentyl, isopentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl,heptyl, octyl, and like C H groupings embracive of fewer than 9 carbonatoms.

The compounds of this invention are variously useful, the free alcohol,3(2-hy'droxyethyl)-4methyl-5-phenyloxazolidine, being valuable as anintermediate both to the corresponding esters hereof and to certainmorpholine derivatives described and claimed in our copending UnitedStates patent application, Serial No. 726,638, filed April 7, 1958, andwhich is a continuation of our application, Serial No. 659,224, filedMay 15, 1957, now abandoned. The morpholine derivatives referred to areanorectic agents capable of substantial and sustained inhibition of theappetite; and, moreover, they are diuretics.

Both the alcohol and esters of this invention are characterized byhighly desirable anti-bacterial and antifungalactivities-representatively, against B. subtilus and Trichophytonmentagrophytes, respectively.

Equivalent to the basic oxazolidines of this invention for the purposeshere described are their acid addition salts, of the formula wherein Rhas the meaning hereinbefore assigned and X is one equivalent of ananion-for example, chloride, bromide, iodide, nitrate, phosphate,sulfate, sulfamate, methyl sulfate, ethyl sulfate, benzenesulfonate,toluenesulfonate, acetate, lactate, succinate, malate, maleate,tartrate, citrate, gluconate, ascorbate, benzoate, cinnamate, or thelike-which, in combination with the anionic portion of a salt aforesaid,is neither pharmacologically nor otherwise undesirable in physiologicaldosage.

Manufacture of 3-(2-hydroxyethyl)-4-methyl-5-phenyloxazolidine proceeds,unexpectedly, by mixing 2-(2'hydroxyethylamino) -1-phenyl-l-propano1 HOOHaCHzNH CH2 HCHOH with aqueous formaldehyde. The corresponding estersderive by heating 3-(2-hydroxyethyl)-4-methyl-5-phenyloxazolidine withpyridine and an appropriate alkanoic acid anhydride. The acid additionsalts of the basic oxazolidines of this invention are obtained by simpleadmixture of the amine base with one equivalent of any of variousinorganic and strong organic acids, the anionic portion of whichconforms to X as hereinabove defined.

Conversion of 3-(2-hydroxyethyl)-4-methyl-5-phenyloxazolidine to thevaluable morpholine derivatives of our Serial Nos. 726,638 and 659,224is eifected by seriatim treatment with a strong acid and a selectedimide ZI-I the compounds so produced having the formula CH3 i 5 CHr-Zbut however that may be, the material which results,

upon heating with the selected imide in a lower alkanol (especiallyethanol) solution, is converted to the corresponding imidomethylmorpholine.

The following examples describe in detail compounds illustrative of thepresent invention and methods which have been devised for theirmanufacture. However, the invention is not to be construed as limited.thereby, either in spirit or in scope, since it will be apparent tothose skilled in the art of organic synthesis that many modifications,both of materials and of methods, may be practiced without departingfrom the purpose and intent of this disclosure. Throughout the exampleshereinafter set forth, temperatures are given in degrees centigrade andrelative amounts of materials in parts by weight, except as otherwisenoted.

Example I thoroughly mixed with 70 parts of 36% formalin. Solid matterdisappears and a heavy oil is formed in process. The resultant mixtureis extracted with chloroform, and the chloroform extract is dried overanhydrous sodium sulfate and stripped of solvent by distillation. Theresidual yellow oil is 3-(2-hydroxyethyl)-4-methyl 5 phenyloxazolidine,of the formula B. 3-(2-hydr0xyethyl)-4-methyl S-phenyloxazolidinehydrochloride.A solution of 3 (2-hydroxyethyl)-4-methyl--phenyloxazolidine in absolute ethanol, made acid with, a slightexcess, of Z-propanolic hydrogen chloride and subsequently diluted withanhydrous ether, affords3-(2-hydroxy'ethyl)-4-methyl-5-phenyloxazolidine hydrochloride as acolorless, hygroscopic, crystalline precipitate which, recovered on afilter and dried in vacuo, meltsat 107-110".

Example 2 S-methybZ-phenyl 4-phthalimia'omethylm0rph0line. To 360 partsof concentrated sulfuric acid at less than 35 is added, portionwise withagitation during 3 hours, the3-(2-hydroxyethyl)-4-methyl-5-phenyloxazolidine obtained by theprocedure of Example 1A. Following the addition, agitation is continuedfor one hour, whereupon the mixture is let stand for hours at roomtemperatures and then neutralized with aqueous caustic in the presenceof suflicient ice (representatively, 200 parts) to insure that thetemperature does not rise above 35". The resultant mixture is extractedwith benzene, and the benzene extract is dried over anhydrous potassiumcarbonate and then stripped of solvent by distillation.

To 21 parts of the yellow oil obtained as the residue, dissolved in 40parts of ethanol, is added, with agitation, 10 parts of phthalimide.Solution occurs. The solution is heated at the boiling point underreflux for 30 minutes, then filtered hot, From the filtrate, on cooling,3-methyl- 2-phenyl 4 phthalimidomethylmorpholine precipitates. Theproduct is collected on a filter and recrystallized from 2-propanol. The3-methyl-2-phenyl-4-phthalimidomethylmorpholine thus obtained melts at142144 and has the formula Example 3 3-methyl-2-phenyl-4succinimidomethylmorpholine. Substitution of approximately 7 parts ofsuccinimide for the 10 parts of phthalimide called for in Example 2afi'ords 3-methyl-2-phenyl-4 succinimidomethylmorpho- 4-. line, meltingat 127-430. The product has the formula Example 4 A. 3(2-acet0xyethyl)-4-methyl-5-phenyl0xaz0lidine.-- To a solution of 44parts of 3(2-hydroxyethyl)-4-methyl- 5-phenyloxazolidine in parts ofpyridine is slowly added, with agitation, approximately 22 parts ofacetic anhydride. Temperature rises to 43 in process. The resultantsolution is agitated at room temperature overnight, then stripped ofsolvent by vacuumdistillation. The residual orange oil is3-(2-acetoxyethyl)-4-methyl-5- phenyloxazolidine, of the formula whereinR is selected from the group consisting of hydrogen and lower alkanoylradicals.

2. 3-(2-hydroxyethyl)-4-methyl-5-phenyloxazolidine. 3. A compound of theformula 4. 3- Z-acetoxyethyl) -4-methyl-5-phenyloxazolidine.

References Cited in the file of this patent UNITED STATES PATENTS2,571,985 Carnes Oct. 16, 1951 FOREIGN PATENTS 388,874 Great BritainMar. 9, 1933 OTHER REFERENCES Goodson et al.: Chemical Abstracts, vol.45, col. 1082 (1951).

1. A COMPOUND OF THE FORMULA